The recent discovery of TRAIL (TNF Related Apoptosis-Inducing Ligand, also known as Apo-2L), has generated considerable excitement among immunologists because of its involvement in down-regulation of the immune response and host defense against tumors. This powerful apoptosis-inducing cytokine has been identified in both humans and mice and is synthesized in many types of cells. Five receptors have been identified: two initiate a signal cascade culminating in apoptosis, two act as cell surface decoys and a fifth is a soluble receptor. Receptor display therefore dictates whether a cell lives or dies. TRAIL and its receptors are abundant at the maternal-fetal interface and are differentially expressed among placental cell lineages. The data acquired to date support the postulate that TRAIL is central to placental immune privilege and has multiple additional functions such as regulating placental growth, differentiation and function. We have designed four Specific Aims to investigate this postulate, as follows: (Aim 1) to establish (a) cell-specific expression of TRAIL and TRAIL-R in human and mouse placentas and trophoblast cell lines and (b) the biochemical and molecular characteristics of human and mouse placental TRAIL; (Aim 2) to investigate regulation of TRAIL and each of its receptors in human and mouse trophoblast cells by placental cytokines (IFN-gamma, TNFalpha), lipopolysaccharide, cAMP and dexamethasone; (Aim, 3) to establish the functions of trophoblast cell TRAIL, evaluating involvement in invasion, expression of cell adhesion molecules and matrix metalloproteinases, hormone synthesis, and, killing capacity and resistance to killing by TRAIL-bearing cells; (Aim 4) to assess potential polymorphisms in the human TRAIL, and TRAIL-R genes, which might influence reproductive success, in collaboration with Dr. C. Ober, University of Chicago. We expect the results of this research to have a major impact on our understanding of the molecular basis for cell-to-cell interactions at the maternal-fetal interface that could ultimately lead to more efficacious therapeutic approaches for improving fertility and reproductive performance in women.